Tau is a central player in the pathogenesis of numerous age-related neurodegenerative diseases, with Alzheimer disease (AD) being the best example. Tau from AD brain is defined by aberrant posttranslational modifications (PTMs), including increases in phosphorylation and acetylation at specific epitopes. The UNDERLYING PREMISE of this proposal is that many of these aberrant PTMs increase tau self-association and toxicity. While the formation of insoluble fibrillary structures is influenced by PTMs, data strongly indicate that soluble forms of abnormally modified tau are the mediators of neuronal toxicity. A CRITICAL KNOWLEDGE GAP is how these modified tau species pathologically impact neuronal function. Additionally, the underlying mechanisms responsible for the increased presence of phosphorylated and acetylated forms in AD have not been fully elucidated. It has been suggested that alterations in how pathologically modified forms of tau are targeted to the autophagic machinery and degraded could be a contributing factor, as well as the fact that they may impair selective autophagy processes. Indeed, there is data indicating that overexpression of AD-relevant forms of tau results in increased levels of fragmented, dysfunctional mitochondria, which may be due to in part due to impaired mitophagy, as well as other perturbations of mitochondrial quality control mechanisms. The OVERALL HYPOTHESIS of this R21 proposal is that AD relevant tau modifications slow tau turnover, impair mitochondrial quality control mechanisms and thus increase the presence of less functional mitochondria with a concomitant increase in oxidative stress and neuronal dysfunction that result in an earlier onset of an aged neuron phenotype. The NOVELTY of this project stems from its use of the model organism C. elegans and its vast repertoire of genetic, transgenic and genomic resources, which has been used extensively to investigate the molecular underpinnings of AD, as well as other tauopathies. Young and older animals will be used to delineate how the presence of these pathological relevant tau species alters these processes as a function of age. The aims of this proposal are to test the hypotheses that: (1) tau acetylated at K274 and K281, tau phosphorylated at T231, or both are not as efficiently turned over as wild type tau and impair mitophagy. C. elegans single copy transgenic models and fluorescent biosensors will be used to address this hypothesis, and (2) tau acetylated at K274 and K281, tau phosphorylated at T231, or both, exacerbate toxicity through chronic mitochondrial stress responses resulting in increased oxidative stress. The relative contribution of these responses to neuronal age-dependent deficits will be further tested using unique genetic resources available in worms. The IMPACT of these studies will be to provide crucial new insights into the mechanisms by which pathological tau species compromise neuronal health and function. They will also provide the foundation for future studies delineating the mechanisms by which specifically modified forms of tau impair neuronal processes and identifying new targets for the development of therapeutics for AD.